DESCRIPTION: The major goal of the proposed study is to comprehensively evaluate the role of genetic susceptibility in the etiology of squamous cell carcinoma of the head and neck (SCCHN; including oral cavity, pharynx, and larynx). SCCHN provides an ideal model for the investigation of gene-environment interaction in cancer given its strong and highly prevalent risk factors, tobacco and alcohol. Polymorphisms in genes representing metabolism (activation and detoxification) of carcinogens, mediators of oxidative stress, and DNA repair may help to clarify dose-response relationships needed for risk assessment, elucidate low dose exposure effects, pinpoint specific carcinogens that act as part of complex mixtures, and to identify susceptible subgroups of individuals most likely to benefit from interventions to reduce exposure. The proposed North Carolina population-based case-control study including 1,700 cases and 1,700 controls will have the ability to more precisely define the nature of the gene-environment interactions related to the risk of SCCHN. This will be the largest study of head and neck cancer ever conducted in the United States. North Carolina is an excellent setting to conduct such a study given the large biracial population, relatively high prevalence of tobacco use, and the research team's experience with conducting population-based molecular epidemiologic studies of cancer. The previous gene-environment studies have yielded generally inconsistent results with respect to several metabolizing enzyme polymorphisms. These studies have been limited by their relatively small size (typically fewer than 200 cases), hospital-based design and examination of a small number of enzymes. The size and population-based design should allow us to more confidently confirm or reject associations raised in previous studies. Finally, the study size will permit us to consider selected gene-gene exposure interactions and examine important subgroups defined by age, gender, race, and tumor site. The systematic collection of tumor blocks will also facilitate future studies of "downstream" somatic alterations of tumor suppressor genes and oncogenes. The proposed study should contribute knowledge on gene-environment interactions for cancer of the head and neck, but also for other tobacco- and alcohol-related cancers and possibly cancers of unknown etiology.